ABSTRACT Opioid abuse rates are exploding in rural and economically distressed communities in the Appalachian region and associated health consequences, including Hepatitis C (HCV) and HIV, are also on the rise. The harmful impact of opioids have received national attention, yet the drivers of the spread of opioid use disorders (OUD) and overdose across communities are not yet understood. In addition, the intertwined relationship between injection opioid drug use and co-morbidities including Hepatitis C and HIV infection necessitate further investigation to inform integrated prevention and intervention efforts. Few studies have used an in-depth, ecologically valid approach to collect information from local community stakeholders with contextually specific experience addressing the epidemic. The overall goal of this one-year planning research grant (in response to RFA-DA-16-015) is to examine contextually- and temporally-specific patterns of the opioid epidemic in the Northern Appalachian Region of Southwestern Pennsylvania using complementary quantitative and qualitative approaches. We propose to use a mixed methods approach incorporating spatial analyses of OUD and overdose hospitalizations and qualitative data from local stakeholders to better understand the spread of opioid injection drug use in the ten counties that make up the Northern Appalachian Region of Southwestern Pennsylvania. The Specific Aims of this proposal are: (1) To characterize the growth and spread of opioid drug abuse, dependence, and overdose and associated co-morbidities (HCV and HIV) over time and space and (2) To identify resources and intervention opportunities associated with opioid drug abuse, dependence, and overdose and associated co-morbidities within one ?hot spot? community. We will combine 16 years of well- resolved spatial data with qualitative data to be collected using a community engaged approach and in-depth interviews in a purposefully sampled target case community. We will start by examining hospital patient spatial data at the ZIP code level to measure the geographic growth and spread of OUD and two comorbid conditions (HCV & HIV) as measured by 64 quarters of inpatient hospitalization data (from 2000 through 2015). We will identify specific attributes of areas (e.g., economic conditions) that facilitate spread over time across ZIP codes, and distinguish the temporal scale of these impacts. Spatial random effects models and posteriors from these models will be used to identify one ?case? community (defined by 2015 ZIP code boundaries) with the greatest predicted probability of comorbid epidemic outbreak. In this case community we will identify and engage key stakeholders, including clinicians & treatment providers (focused on opioids, HCV, and HIV), and others (e.g. former opioid injection users) identified through snowball sampling. We will use qualitative interviews with 20 informants to identify drivers of the intersecting epidemics and existing resources and novel intervention opportunities. This work will lay the foundation for larger action-oriented research and planning efforts addressing opioid injection drug use, HCV and HIV in the Appalachian region.